Basic Tilted Helix Bundle - a new protein fold in human FKBP25/FKBP3 and HectD1

Abstract

In this paper, we describe the structure of a N-terminal domain motif in nuclear-localized FKBP251-73, a member of the FKBP family, together with the structure of a sequence-related subdomain of the E3 ubiquitin ligase HectD1 that we show belongs to the same fold. This motif adopts a compact 5-helix bundle which we name the Basic Tilted Helix Bundle (BTHB) domain. A positively charged surface patch, structurally centered around the tilted helix H4, is present in both FKBP25 and HectD1 and is conserved in both proteins, suggesting a conserved functional role. We provide detailed comparative analysis of the structures of the two proteins and their sequence similarities, and analysis of the interaction of the proposed FKBP25 binding protein YY1. We suggest that the basic motif in BTHB is involved in the observed DNA binding of FKBP25, and that the function of this domain can be affected by regulatory YY1 binding and/or interactions with adjacent domains.

Keywords: FKBP25; FKBP3; HectD1; Immunophillins; NMR structure; Structural genomics; YY1.

Fig. 1

Sequence alignment (a) between FKBP25_1-73and HectD1_1879-1966, with every tenth amino acid in each sequence marked by a dot. Structurally non-equivalent residues (e.g. in loops) are in lowercase. Stereo view of FKBP25_1-73 (b) and HectD1_1879-1966(c), with the backbone displayed for all the 20 conformers and the side chains only for the lowest energy one, for the sake of clarity. (d) Superimposed backbone representation (oxygen atom of the peptide bond excluded) for FKBP25_1-73 (blue) and HectD1_1879-1966(orange); the loops are illustrated with in a lihter shade, compared to the helices. (For interpretation of the references to colours in this figure legend, the reader is referred to the web version of this paper).

Fig. 2

Ribbon diagram (a, d) and electrostatics surface (b and e) for the structure of FKBP25_1-73 (a and b) and HectD1_1879-1966 (d and e), respectively. Surface-exposed, evolutionary conserved residues (orange) and YY1 interaction surface (magenta) are highlighted in (c) for FKBP25_1-73. The electrostatic surface representations were rotated of an appropriate angle in the last view to show in the best way for each structure the wide electrostatic patch. (For interpretation of the references to colours in this figure legend, the reader is referred to the web version of this paper).